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The GATOR2 Component Wdr24 Regulates TORC1 Activity and Lysosome Function.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Metabolism

Background:

  • TORC1 is a central regulator of eukaryotic metabolism, responding to various signaling pathways.
  • The GATOR complex, comprising GATOR1 and GATOR2, modulates TORC1 activity.
  • GATOR1's role in pathologies is known, but GATOR2's in vivo function in metazoans is unclear.

Purpose of the Study:

  • To investigate the in vivo role of Wdr24, a GATOR2 component, in Drosophila.
  • To elucidate Wdr24's functions in cellular metabolism and TORC1 signaling.
  • To explore Wdr24's potential TORC1-independent roles.

Main Methods:

  • Genetic analysis using a Wdr24 null allele in Drosophila.
  • Biochemical and cell biological techniques.
  • Epistasis analysis with GATOR1 complex genes.
  • Characterization of a Wdr24 knockout HeLa cell line.

Main Results:

  • Wdr24 is essential for TORC1 activation and cellular growth in Drosophila.
  • Wdr24 exhibits TORC1-dependent and independent functions.
  • Wdr24, Mio, and Seh1 regulate lysosome dynamics and autophagic flux independently of TORC1.
  • Wdr24 promotes lysosome acidification and autophagic flux in mammalian cells.

Conclusions:

  • Wdr24 is a key effector of the GATOR2 complex.
  • Wdr24 is crucial for TORC1 activation and cellular growth.
  • GATOR2 components have a novel, unappreciated role in regulating lysosome function and autophagy.